The fundamenal neuroscientific question as to how myelinating glia promote the health of long axons is greatly understudied. Axons are a particularly vulnerable component of neural circuits that are irreversibly damaged in early stages of many debilitating neurodegenerative conditions such as Multiple sclerosis and Alzheimers? disease. The mechanisms underlying glial contributions to axonal injury are only pooly understood. Oligodendrocytes (OLGs), the myelinating glia of the central nervous system, stabilize axonal integrity by poorly understood trophic mechanisms. Current models suggest that glial metabolism is critical for this support function, and disrupted metabolic exchange between OLGs and axons, or metabolic deficits in OLGs may lead to axonal degeneration. In support, we made the exciting discovery that the LKB1 (liver kinase B1) signaling pathway is a crucial metabolic regulator in OLGs, and the inactivation of LKB1 in these glia results in aberrant mitochondrial energy metabolism and progressive degeneration of axons. Remarkably, such non-cell-autonomous axon degeneration is not preceded by changes of OLG structure and myelination, indicating that it occurs secondary to glial metabolic perturbation. These discoveries lead us to hypothesize that LKB1 and its downstream metabolic effectors, most notably those regulating mitochondrial metabolism in OLGs, are integral to the trophic support mechanisms for axons. Using manipulation of LKB1 signaling as an experimental tool to change glial metabolism with no impact on other biological outputs of OLGs, here we implement a multidisciplinary approach that will afford us the unique opportunity to pinpoint metabolic alterations in OLGs that disrupt the support of axons. In this context we will also investigate whether axons degenerate as a consequence of energetic deprivation, or metabolic poisoining. Together, this will provide valuable data to elucidate which downstream components of the LKB1-dependent metabolic signaling network in OLGs are fundamentally important for axon integrity. The proposed efforts may open the door to the identification of unexpected metabolic components in OLGs that are essential for axon support. Manipulation of these components will have the potential to promote axon integrity in neurodegenerative diseases. Because glial and metabolic abnormalities associated with axon degeneration can be observed in many neurodegenerative conditions, this approach has the potential for wide-ranging therapeutic impact.